Virtual Cell (VCell) is a problem solving environment, built on a central database, for analysis, modeling and simulation of cell biological processes. VCell integrates a growing range of molecular mechanisms, including reaction kinetics, diffusion, flow, membrane transport, lateral membrane diffusion and electrophysiology, and can associate these with geometries derived from experimental microscope images. The National Resource for Cell Analysis and Modeling (NRCAM) has as its mission the growth of the VCell technology via research at the interface of physics, mathematics, computer science and biology. NRCAM is housed in a research center comprising an interdisciplinary faculty and containing state of the art facilities for studying living cells. This environment assures that experiment and theory drive each other synergistically. The technology research of this application is divided into 4 projects. Biophysical Mechanisms extends VCell into the domains of macromolecular aggregation, cytoskeletal dynamics and spatial electrophysiology, each of which can be treated in only a limited way with the current VCell. Numerical Tools will develop stiff solvers, adaptive meshing and parallelization to improve the efficiency and increase the size and complexity of spatial simulations;this project will also develop an elliptic solver to extend VCell simulations to biomechanics, spatial electrophysiology and steady state analysis. Enabling Technologies proposes to revise VCell by adopting a plugin architecture and augmenting the abstract software layers with a new multiphysics layer;these will effectively manage the complexity of the overall system to accommodate rapid application development. The Application Development project is charged with implementing enhancements for VCell through both internal development (e.g. grid computing, stand-alone VCellApps and visualization tools) and adoption of an open software development model that will encourage external contributions. Thirteen collaborative projects designed to drive the VCell development with investigators from around the US are described. Through training, dissemination and collaborative activities, NRCAM promotes a quantitative approach to cell biological research. VCell represents an advanced tool for investigations of the cellular basis of disease, especially as related to the cardiac, nervous and immune systems and cancer. As the database of models expands, simulating drug actions and side effects will become increasingly feasible.